Research on Safety of Electronic Cigarettes Slides from Dr. Konstantinos Farsalinos' presentation at the E-Cigarette Summit, London November 12, 2013. Full summary of the E-Cigarette Summit: http://ecigarettereviewed.com/e-cigarette-summit-london-summary

1. Research on safety of
electronic cigarettes
Dr. Konstantinos Farsalinos
Researcher, Onassis Cardiac Surgery Center, Athens, Greece
Researcher, Department of Cardiovascular Diseases, University Hospital
Gathuisberg, Leuven, Belgium

2. E-cigarette facts
• New in the market
• Developed due to inefficiency of currently approved methods for
smoking cessation
• NRTs < 6% success rate (Moore et al., BMJ 2009)
• Oral medications < 20% success rate (Rigotti et al., Circulation
2010)
• Awareness and use growing exponentially
• Used by millions, mostly of young age (40 yo)
• Nicotine delivery, dealing with behavioral addiction
• No tobacco, no combustion
• Any regulation should be based on scientific evidence

3. Safety studies
• Laboratory
▫ Chemical
▫ Toxicology
• Clinical
▫ Pathophysiology (short-term)
▫ Epidemiology (long-term)

4. Safety studies
• Laboratory
▫ Chemical
▫ Toxicology
• Clinical
▫ Pathophysiology (short-term)
▫ Epidemiology (long-term)

5. Chemical studies
• Most commonly performed (mostly on liquids, fewer on
vapor)
• More than 300 analyses in Greece for presence of
TSNAs+PAH
• Provide indirect evidence on safety
• Findings depend on what you search for
• Flavorings used are GRAS for use in food
• We don’t know implications when inhaled
• Example of diacetyl -> bronchiolitis obliterans

6. Chemical studies
Cahn & Siegel, J Public Health Policy 2011

7. Chemical studies
Farsalinos et al, J Chromatogr A, 2013
Kim & Shin, J Chromatogr A 2013

8. Chemical studies
Goniewicz et al, Tob Control 2013

9. Chemical studies
Overheating may lead to
production of toxic chemicals
Huge variety of devices, with different battery, liquid capacity and resistance.
HOWEVER, all were handled in the same way (2-seconds puff every 10 seconds)
Unrealistic conditions
Goniewicz et al, Tob Control 2013

10. Chemical studies
Despite that
Goniewicz et al, Tob Control 2013

11. Chemical studies
We need more studies on ecigarette materials
Williams et al, PLoS One 2013

12. Chemical studies
Passive vaping
Schripp et al, Indoor Air 2013

13. Chemical studies
Passive vaping
Schripp et al, Indoor Air 2013

14. Chemical studies
Passive vaping
Romagna, Farsalinos et al, SRNT Europe 2012

15. Chemical studies
Passive vaping
Romagna, Farsalinos et al, SRNT Europe 2012

16. Safety studies
• Laboratory
▫ Chemical
▫ Toxicology
• Clinical
▫ Pathophysiology (short-term)
▫ Epidemiology (long-term)

17. Safety studies
• Laboratory
▫ Chemical
▫ Toxicology
• Clinical
▫ Pathophysiology (short-term)
▫ Epidemiology (long-term)

18. Toxicology studies
Main problem
Test on LIQUID,
not on VAPOR
Bahl et al, Reprod Toxicol 2012

19. Toxicology studies
Tests on vapor
Dilutions
Extracts
Tuscan1
Black fire1
Ozone1
Reggae night1
Vanilla
7foglie1
Max blend1
Virginia1
Perique black1
Layton blend1
Hypnotic1
Hazelnut
Shade1
RY41
Strawberry
Managua
Burley
Apple
Licorice
Chocolate
Coffee
CS
100%a
50% b
25% c
94.5 ± 2.8
96.3 ± 9.9
90.7 ± 9.9
81.3 ± 5.1
100 ± 2.4
81.4 ± 2.9
96.2 ± 6.0
78.4 ± 14.4
79.3 ± 1.5
101.1 ± 1.0
93.8 ± 10.8
88.7 ± 1.4
83.6 ± 5.1
88.4 ± 8.1
85.8 ± 2.8
79.1 ± 2.4
102.2 ± 3.4
95.2 ± 1.2
95.4 ± 3.9
87.6 ± 2.2
51.0 ± 2.6
5.7 ± 0.7
99.8 ± 5.7
93.4 ± 2.5
95.9 ± 9.1
90.3 ± 3.7
98.5 ± 3.5
87.5 ± 1.5
97 ± 6.9
86.1 ± 13.5
89.8 ± 2.4
103.7 ± 0.8
95.2 ± 14.0
90.1 ± 5.6
92.5 ± 3.9
96.1 ± 3.7
95.4 ± 2.3
79.9 ± 3.3
95.8 ± 2.9
87.4 ± 2.7
93.9 ± 2.8
89.6 ± 0.6
85.9 ± 11.8
9.4 ± 5.3
104 ± 1.5
94.4 ± 1.6
96.2 ± 4.3
89.5 ± 4.2
100.3 ± 2.0
89.4 ± 4.0
102.1 ± 7.4
91.3 ± 15.6
94.7 ± 1.2
102.7 ± 2.8
106.2 ± 6.5
93.5 ± 6.7
94.6 ± 5.0
98.7 ± 6.4
97.5 ± 1.5
79.1 ± 3.1
97.6 ± 1.3
100.8 ± 8.2
96.5 ± 2.6
93.2 ± 1.3
92.0 ± 8.9
5.9 ± 0.9
12.5% d
101.4 ± 4.1
104.6 ± 2.9
94.9 ± 6
89.7 ± 3.4
100.1 ± 0.8
87.1 ± 8.3
111.8 ± 4.5
96.4 ± 16.2
95.3 ± 5.2
100.6 ± 2.1
97.4 ± 5.1
91.5 ± 1.5
97.8 ± 5.9
95.8 ± 7.4
104.0 ± 6.2
85.8 ± 2.0
97.3 ± 3.4
95.6 ± 3.9
98.5 ± 4.4
93.4 ± 1.5
101.5 ± 3.1
72.8 ± 9.7
6.25% e
100.7 ± 5.9
95.3 ± 4.3
96.7 ± 5.1
90.2 ± 5.7
104.1 ± 3.1
89.6 ± 12.1
114.3 ± 1.7
106.3 ± 9.7
95.1 ± 2.4
103.4 ± 5.5
100.6 ± 7.4
115.3 ± 8.0
101.5 ± 2.5
98.9 ± 6.3
99.6 ± 1.4
86.4 ± 1.7
106.2 ± 8.3
101.8 ± 3.1
98.9 ± 2.0
93.7 ± 1.9
112.2 ± 3.6
77.8 ± 1.8
3.125% f
98.6 ± 3.8
97 ± 3.2
97 ± 4.9
91.6 ± 4.2
98.3 ± 3.3
93.2 ± 10.7
115.5 ± 5.3
104.4 ± 10.7
93.9 ± 3.4
97.9 ± 4.2
98.5 ± 3.9
117.8 ± 13.4
101.9 ± 1. 3
98.9 ± 5.9
107.5 ± 1.2
88.5 ± 3.5
100.5 ± 6.2
106.6 ± 15.6
99.6 ± 2.5
98.9 ± 1.2
114.5 ± 1.1
89.1 ± 3.5
P*
0.216
0.159
0.879
0.132
0.183
0.587
0.003
0.478
< 0.001
0.295
0.579
0.001
0.002
0.378
< 0.001
0.002
0.171
0.106
0.252
< 0.001
<0.001
< 0.001
Romagna, Farsalinos et al, Inhal Toxicol 2013

20. Toxicology studies
Tests on vapor
Relative difference in viability between
cigarette smoke and worst-performing vapor
extract
Romagna, Farsalinos et al, Inhal Toxicol 2013

21. Toxicology studies
Tests on vapor
Myocardial cells
Farsalinos et al, Int J Environm Res Public Health 2013

22. Farsalinos et al, Int J Environm Res Public Health 2013

23. Toxicology studies
Tests on vapor
Myocardial cells
Untreated cells
E-cigarette
vapor treated
cells
Cigarette smoke
treated cells
Farsalinos et al, Int J Environm Res Public Health 2013

24. Toxicology studies
Cinnamon toxicity (?)
Tests on liquid
Irrelevant to e-cig
Approved
cinnamaldehyde dose
up to 4 x 10-2 M
(EPA, 2000)
Behar et al, Toxicol in Vitro 2013

25. Safety studies
• Laboratory
▫ Chemical
▫ Toxicology
• Clinical
▫ Pathophysiology (short-term)
▫ Epidemiology (long-term)

26. Safety studies
• Laboratory
▫ Chemical
▫ Toxicology
• Clinical
▫ Pathophysiology (short-term)
▫ Epidemiology (long-term)

27. Clinical studies
• Few studies performed on safety
• Long-term studies cannot be performed
• May get valuable information from studies on
pathophysiology of smoking-related disease,
immediate effects of use, short-term follow-up
and surveys

28. Clinical studies
Nicotine levels in e-cigarette unlikely to cause
overdose
•
•
•
•
Experienced e-cigarette users
5 minutes-13 puffs
Liquid consumption: 0.052 ± 0.13ml
Nicotine consumption: ≈ 1mg from 18mg/ml
nicotine-containing liquid
• Levels of nicotine absorption lower than
smoking (Dawkins et al, 2013)
Farsalinos et al, Subst Abuse 2013

29. Clinical studies
High nicotine levels
important in complete
substitution of
smoking (111 users)
Farsalinos et al, Subst Abuse 2013

30. Clinical studies
Effects on lung function
•No mention on changes in FEV1/FVC
•Could be due to short-term mechanical irritation and not damage
•Data from surveys report temporary cough as initial symptom
•No comparison with regular cigarettes
Vardavas et al, Chest 2012

31. Clinical studies
Effects on lung function
Flouris et al, Inhal Toxicol 2013

32. Clinical studies
Effects on cardiac function
Smokers (n=20)
ECIG users (n=22)
P-value
36 ± 5
36 ± 5
0.971
Body-mass index (kg/m2)
25.3 ± 2.5
26.5 ± 2.4
0.129
Body-surface area (m2)
2.02 ± 0.22
2.09 ± 0.15
0.292
Systolic BP (mmHg)
125 ± 10
127 ± 9
0.479
Diastolic BP (mmHg)
76 ± 6
77 ± 7
0.913
Heart rate (per minute)
67 ± 8
67 ± 9
0.915
LVEDV (ml)
115 ± 23
120 ± 22
0.459
LVESV (ml)
45 ± 8
47 ± 10
0.492
SV (ml)
70 ± 17
73 ± 14
0.497
Ejection fraction (%)
60 ± 4
61 ± 4
0.578
LAd
35 ± 4
34 ± 4
0.688
LAVi (ml/m )
22 ± 5
20 ± 5
0.122
LVMi (g/m2)
63 ± 10
68 ± 13
0.154
Age (years)
2
Farsalinos et al, ESC 2012-Munich

33. Clinical studies
Effects on cardiac function
Hemodynamic changes
Post-use
P-value
P-value (ECIG P-value (inter(smokers
users intragroup after
intra-group)
group)
inhalation)
Smokers
(n=20)
ECIG users
(n=22)
SBP (mmHg)
135 ± 7
128 ± 10
< 0.001
0.433
0.028
DBP (mmHg)
80 ± 7
81 ± 6
< 0.001
0.001
0.57
HR bpm
74 ± 8
68 ± 10
< 0.001
0.245
0.055
Ejection fraction (%)
60 ± 4
62 ± 4
0.317
0.224
0.571
Farsalinos et al, ESC 2012-Munich

34. Clinical studies
Effects on cardiac function
P = 0.011
P = 0.005
Sm
Em
Am
Sm
Em
Am
Farsalinos et al, ESC 2012-Munich

35. Clinical studies
Effects on cardiac function
P = 0.01
P = 0.042
*P = 0.01
¶P = 0.005
¶
¶
0.6
*
*
MPI
tMPI
MPI
tMPI
0.6
5.6 ± 1
0.4
0.4
0.2
0.2
0.0
0.0
Farsalinos et al, ESC 2012-Munich

36. Clinical studies
CFVR = velocitypost-adenosine / velocitybaseline
CVRI = (MAP / velocity)post-adenosine / (MAP / velocity)baseline
60 participants
Farsalinos et al, ESC 2013-Amsterdam

37. Clinical studies
Smokers / cigarette
4
CFVR
16%
2.90 ± 0.49
4
P < 0.001
19%
0.70
P < 0.001
0.60
2.45 ± 0.45
3
CVRI
0.70
3
0.60
0.416 ± 0.077
0.50
0.50
0.351 ± 0.067
0.40
0.30
0.30
0.20
0.20
0.10
2
0.40
0.10
0.00
0.00
2
1
1
0
0
Baseline
Post-smoking
Baseline
Post-smoking
Farsalinos et al, ESC 2013-Amsterdam

38. Clinical studies
Smokers / e-cigarette
CFVR P = NS
4
2.90 ± 0.49
CVRI P = NS
3
3
0.70
0.70
0.60
2.93 ± 0.62
4
0.60
0.50
0.351 ± 0.067
0.353 ± 0.079
0.50
0.40
0.30
0.30
0.20
0.20
0.10
2
0.40
0.10
0.00
0.00
2
1
1
0
0
Baseline
Post-use
Baseline
Post-use
Farsalinos et al, ESC 2013-Amsterdam

39. Clinical studies
E-cigarette users
CFVR P = NS
4
2.99 ± 0.55
CVRI P = NS
0.70
3.05 ± 0.64
3
0.70
4
0.60
3
0.60
0.50
0.50
0.341 ± 0.062
0.337 ± 0.075
0.40
2
1
1
0
0
Baseline
Post-use
0.30
0.30
0.20
0.20
0.10
2
0.40
0.10
0.00
0.00
Baseline
Post-use
Farsalinos et al, ESC 2013-Amsterdam

40. Clinical studies
Carboxyhemoglobin
Smokers
* P < 0.001
Ecig users
P = NS
6
6
5
5
5
4
4
4
3
3
3
3
2
2
2
2
6
3.50 ± 1.11*
5
2.93 ± 1.15
4
2.88 ± 1.10
0.81 ± 0.20
6
0.80 ± 0.21
1
1
1
1
0
0
0
0
Baseline
Post-cigarette Post-ecig
Baseline
Post-ecig
Farsalinos et al, ESC 2013-Amsterdam

41. Clinical studies
More to come…
• Effect on aortic elasticity (EUROECHO 2013)
• Effect on pulsed-wave velocity (measure of
arterial stiffness)
• Always comparison with tobacco cigarettes

42. Clinical studies
What we need to know
• Long-term safety cannot be assessed unless 10-15 years
have passed, because:
 Smoking causes disease after many years of use
 Current e-cigarette users are of young age (disease
incidence is very low in this population)
 E-cigarette is a new product

43. Clinical studies
What we need to know
• Lung function:
 Need to compare with tobacco cigarettes
 Acute lung dysfunction may be caused by pure mechanical
irritation, which does not predict harm (e.g. cold weather)
 Surveys have shown some irritation which is temporary, with
subsequent beneficial effects (subjectively perceived)
• Cardiac function:
 Variety of mechanisms by which smoking causes disease
 Some of smoking adverse effects take long time to reverse (e.g.
inflammatory markers)

44. Conclusions
• Although there are several chemical studies, few are performed on
vapor
• Need for more toxicology studies
• Need for studies on atomiser materials
• Protocol and device handling are the most crucial factors in getting
results applicable to real use
• Clinical studies are scarce; some already scheduled, need more
• Long-term studies impossible right now
Based on currently available data, it is reasonable to expect a
significant benefit for the health of smokers who switch from
tobacco to e-cigarette use, even in long-term users.

45. Conclusions
Research will help us define the best possible
materials in e-liquids and devices, which should
be done without killing variability and
innovation